Drug delivery devices with drug-permeable component and methods

ABSTRACT

Implantable drug delivery devices include a housing having a closed drug reservoir lumen bounded by a first wall structure and a hydrophilic second wall structure, and a drug contained in the drug reservoir lumen, wherein the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. Methods of providing controlled release of drug to a patient include deploying a drug delivery device in the patient releasing a drug from the drug reservoir lumen via diffusion through the second wall structure.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/799,733, filed Mar. 15, 2013, which is incorporated herein byreference.

BACKGROUND

The present disclosure is generally in the field of implantable medicaldevices, and more particularly relates to drug-delivery devices with adrug-permeable component.

Implantable medical devices and methods are known for targeted, e.g.,local or regional, drug delivery in order to avoid the problemsassociated with systemic drug delivery. Local delivery of drug to sometissue sites, however, has room for improvement, particularly withrespect to extended drug delivery with minimally invasive devices andmethods with minimum patient discomfort from the presence of the deviceitself. The problem is particularly acute for certain drugs, e.g., thosehaving relatively low water solubility, and/or for certain therapies inwhich the drug needs to be controllably released at therapeutic levelsover an extended periods of several days or weeks, while keeping thedevices sufficiently small to avoid unnecessary discomfort and painduring and following deployment of the device into patient.

U.S. Patent Application Publications No. 2012/0203203 (TB 121), No.2012/0089122 (TB 117), No. 2011/0060309 (TB 108), No. 2011/0152839 (TB112), and No. 2010/0331770 (TB 101) by TARIS Biomedical Inc. describevarious drug delivery devices that provide controlled release of drugfrom a housing. The device may be free floating in a patient's bladder,yet tolerably and wholly retained in the patient's bladder while locallyreleasing the drug over an extended period. It would be desirable,however, to provide new designs of intravesical drug delivery devices,and other implantable devices capable of delivering drugs at effectiverelease rates for a range of different drugs.

SUMMARY

In one aspect, implantable drug delivery devices are provided, includinga housing having a closed drug reservoir lumen bounded by a first wallstructure and a hydrophilic second wall structure, and a drug containedin the drug reservoir lumen, wherein the first wall structure isimpermeable to the drug, and the second wall structure is permeable tothe drug. In one embodiment, the first wall structure is a cylindricaltube and the second wall structure is an end wall disposed at at leastone end of the cylindrical tube. In another embodiment, the first wallstructure and the second wall structure are adjacent one another andtogether form a cylindrical tube.

In another aspect, methods of providing controlled release of drug to apatient are provided, including (i) deploying a drug delivery device inthe patient, the device comprising a closed drug reservoir lumen boundedby a first wall structure and a hydrophilic second wall structure, and(ii) releasing a drug from the drug reservoir lumen via diffusionthrough the second wall structure, wherein the first wall structure isimpermeable to the drug, and the second wall structure is permeable tothe drug. In one embodiment, the first wall structure is a cylindricaltube and the second wall structure is an end wall disposed at at leastone end of the cylindrical tube. In another embodiment, the first wallstructure and the second wall structure are adjacent one another andtogether form a cylindrical tube.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 2 is a cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 3 is a cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 4A is an exploded perspective view of a portion of one embodimentof an implantable drug delivery device wherein the second wall structureis an end wall.

FIG. 4B is a perspective view of the portion of the device of FIG. 4A.

FIG. 4C is a cross-sectional perspective view of the portion of thedevice of FIG. 4B.

FIG. 4D is a cross-sectional view of the portion of the device of FIG.4B.

FIG. 5 is a partial cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 6 is a partial cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 7 is a partial cross-sectional plan view of one embodiment of animplantable drug delivery device wherein the second wall structure is anend wall.

FIG. 8A is a plan view of one embodiment of an implantable drug deliverydevice wherein the second wall structure is an end wall.

FIG. 8B is a cross-sectional view of the device of FIG. 8A.

FIG. 9 is a cross-sectional view of one embodiment of an implantabledrug delivery device wherein the first and second wall structurestogether form a cylindrical tube.

FIG. 10A is an exploded perspective view of one embodiment of animplantable drug delivery device wherein the first and second wallstructures together form a cylindrical tube.

FIG. 10B is a perspective view of the device of FIG. 10A.

FIG. 10C is a partial cross-sectional perspective view of the device ofFIG. 10B.

FIG. 11A is an exploded perspective view of one embodiment of animplantable drug delivery device wherein the first and second wallstructures together form a cylindrical tube.

FIG. 11B is a cross-sectional plan view of the device of FIG. 11A.

FIG. 12A is an exploded perspective view of one embodiment of animplantable drug delivery device wherein the first and second wallstructures together form a cylindrical tube.

FIG. 12B is a perspective view of the device of FIG. 12A.

FIG. 12C is a cross-sectional view of the device of FIG. 12B.

FIG. 13 is a graph showing the cumulative amount of gemcitabine HClreleased from a HP-93A-100 pouch over time.

FIG. 14 is a graph showing the cumulative amount of gemcitabine basereleased from a HP-93A-100 pouch over time.

FIG. 15 is a graph showing the cumulative amount of gamma irradiatedgemcitabine HCl released from a HP-93A-100 pouch over time.

FIG. 16 is a graph showing the cumulative amount of gemcitabine HClreleased from a HP-60D-60 pouch over time.

FIG. 17 is a graph showing the cumulative amount of gemcitabine basereleased from a HP-60D-60 pouch over time.

FIG. 18 is a graph showing the cumulative amount of gamma irradiatedgemcitabine HCl released from a HP-60D-60 pouch over time.

FIG. 19 is a graph showing the percent amount of gemcitabine HClreleased from a HP-93A-100 pouch over time.

FIG. 20 is a graph showing the percent amount of gemcitabine basereleased from a HP-93A-100 pouch over time.

FIG. 21 is a graph showing the percent amount of gamma irradiatedgemcitabine HCl released from a HP-93A-100 pouch over time.

FIG. 22 is a graph showing the percent amount of gemcitabine HClreleased from a HP-60D-60 pouch over time.

FIG. 23 is a graph showing the percent amount of gemcitabine basereleased from a HP-60D-60 pouch over time.

FIG. 24 is a graph showing the percent amount of gamma irradiatedgemcitabine HCl released from a HP-60D-60 pouch over time.

FIG. 25 is a graph showing the release rate of gemcitabine from deviceshaving drug permeable end wall disks of varying size, over time.

FIG. 26 is a graph showing the release rate of gemcitabine from staticand rotated devices having drug permeable end wall disks, over time.

FIG. 27 is a graph showing the release rate of gemcitabine from a devicehaving a drug permeable end wall disk at one end, over time.

FIG. 28 is a graph showing the release rate of gemcitabine from staticand rotated devices having drug permeable end wall disks, over time.

FIG. 29 is a graph showing the cumulative amount of gemcitabine releasedfrom static and rotated devices having drug permeable end wall disks,over time.

FIG. 30 is a graph showing the percent amount of gemcitabine releasedfrom static and rotated devices having drug permeable end wall disks,over time.

FIG. 31 is a graph showing the release rate of gemcitabine from staticand rotated devices having drug permeable end wall disks, over time.

FIG. 32 is a graph showing the cumulative amount of gemcitabine releasedfrom a four module device having drug permeable end wall disks, overtime.

FIG. 33 is a graph showing the in vivo urine concentration of2′,2′-difluoro-2′-deoxyuridine (dFdU) at various times.

FIG. 34 is a graph showing the cumulative amount of tropsium chloridereleased from a single module device having a drug permeable end walldisk at one end, over time.

FIG. 35 is a graph showing the cumulative amount of tropsium chloridereleased from a single module device having a drug permeable end walldisk at one end, over time.

FIG. 36 is a graph showing the cumulative amount of lidocaine HClreleased from a single module device having a drug permeable end walldisk at one end, over time.

FIG. 37 is a graph showing the cumulative amount of lidocaine HClreleased from a device having first and second wall structures that areadjacent one another and form a cylindrical tube, over time.

DETAILED DESCRIPTION

Improved implantable drug delivery devices are provided. In a particularembodiment, the devices are configured for intravesical insertion andsustained drug delivery, preferably providing a zero order release rateof therapeutically effective amounts of the drug.

It was discovered that it may be difficult to achieve a zero orderrelease rate beyond three to four days with osmotic pressure deliverymechanisms for certain drugs. In experiments, after three to four days,the drug release rate quickly decreased, which can cause the drug urineconcentration in the bladder to fall below a minimum effectiveconcentration before the end of treatment period. It is not alwaysfeasible to extend the period of zero order release simply by providingmore, or more densely packed, osmotic agent with the drugs, for exampledue to overall implant system size limitations. It is also not alwaysfeasible to instead provide overall first order drug release during anentire treatment period, because it may not be safe to have the initialpeak drug release rate high enough that even with the decay of the drugrelease rate toward the end of the treatment period, the release rate isstill above minimum effective concentration of the drug.

Accordingly, the particular devices described herein have beendeveloped, wherein instead of an osmotic drug release mechanism, drugrelease is controlled by drug diffusion through a drug-permeable polymeror matrix component defining part of the device housing. In oneembodiment, the device includes a drug-permeable polymer component.

In one aspect, an implantable drug delivery device is provided thatincludes a housing having a closed drug reservoir lumen bounded by afirst wall structure and a hydrophilic second wall structure; and a drugcontained in the drug reservoir lumen, wherein the first wall structureis permeable or impermeable to water and impermeable to the drug, andthe second wall structure is permeable to the drug. The walls boundingand defining the drug reservoir of the device are made of a firstmaterial that serves as the first wall structure and a second materialthat serves as the second wall structure, such that drug release occursessentially only through the second material. In one embodiment, thedevice does not include an aperture; drug release is only by diffusionthrough the second wall structure. As used herein, the terms“impermeable to the drug” and “impermeable to water” refer to the wallstructure being substantially impermeable to the drug or to water, suchthat essentially no drug or water is released via the wall structureover the therapeutic release period.

For use in the bladder, it is important that the device be compliant(i.e., easily flexed, soft feeling) during detrusor muscle contractionin order to avoid or mitigate discomfort and irritation to the patient.Thus, it is noted the durometer of the first and second materials ofconstruction are important, and the proportion of a high durometermaterial may be limited in constructing a device housing of a given sizewhile keeping it suitably compliant in the bladder. For example,Tecophilic™ thermoplastic polyurethane (Lubrizol Corp.) may have a Shorehardness greater than 70A, such as from 80A to 65D, while siliconetubing which may have a Shore hardness of from 50A to 70A. Accordingly,it can be advantageous to utilize the combination of these two differentpolymeric materials, rather than making the device entirely of thewater-swelling hydrophilic, drug-permeable second material.

In a preferred embodiment, the device is elastically deformable betweena relatively straightened shape suited for insertion through the urethraof a patient and into the patient's bladder and a retention shape suitedto retain the device within the bladder. In one embodiment, the devicefurther includes retention frame lumen and a retention frame positionedin the retention frame lumen. In embodiments, a retention frame mayinclude two or more housing units.

The first wall structure may be formed of a silicone. For example, thehousing may include a silicone tube, the wall of the silicone tubeserving as the first wall structure. In other embodiments, the firstwall structure may be formed of other water permeable materials. In apreferred embodiment, the drug is in a solid form (e.g., a tablet orplurality of tablets) and the first wall structure is water permeable topermit in vivo solubilization of the drug while in the drug reservoirlumen. For example, the first wall structure may be formed of siliconehaving a Shore durometer value from about 50A to about 70A.

The second wall structure is a hydrophilic polymer, which is designed toabsorb water. For example, the second wall structure may be ahydrophilic elastomeric material, which is at least partially made ofhydrophilic polyurethane, hydrophilic polyesters, or hydrophilicpolyamides. In a preferred embodiment, the second wall structureincludes a thermoplastic polyurethane, such as Tecophilic™ thermoplasticpolyurethane, HydroThane™ thermoplastic polyurethane (AdvanSourceBiomaterials Corp.), Quadraphilic™ thermoplastic polyurethane(Biomerics, LLC) (ALC grades are aliphatic polycarbonate-based and ALEgrades are aliphatic polyether-based hydrophilic polyurethanes),HydroMed™ (AdvanSource Biomaterials Corp.), or Dryflex® (HEXPOL TPE).Another hydrophilic polymer is polyether block amide Pebax® MV 1074 SA01 MED (Arkema), which is a thermoplastic elastomer made of flexible andhydrophilic polyether and rigid polyamide. For example, the hydrophilicmaterial of the second wall structure may have a Shore durometer valuefrom about 70A to about 65D. The particular material and its thicknessand wall area can be selected to achieve a particular drug releaseprofile, i.e., water and drug permeation rates.

The arrangement of the first and second wall structures can take avariety of forms. Non-limiting examples are shown in FIGS. 1-12C. Incertain embodiments, the first wall structure is a cylindrical tube andthe second wall structure is an end wall disposed at least one end ofthe cylindrical tube, or the first wall structure and the second wallstructure are adjacent one another and together form a cylindrical tube.That is, drug release is controlled by drug diffusion through adrug-permeable component defining a portion of the closed devicehousing. The drug-permeable wall structure may be located, dimensioned,and have material properties to provide the desired rate of controlleddrug diffusion from the device.

In one embodiment, as shown in FIGS. 1-8B, the first wall structure is acylindrical tube and the second wall structure is an end wall disposedat least one end of the cylindrical tube. In certain embodiments, thefirst wall structure is a cylindrical tube and the second wall structureis an end wall disposed at least one end of the cylindrical tube and thesecond wall structure is in the form of a disk stabilized in a lumen ofthe cylindrical tube. As shown, the first wall structure may be in theform of a cylindrical tube and the second wall structure may be in theform of a disk at one or both ends. The disk may be stabilized in thelumen of the cylindrical tube using a variety of mechanical or adhesivemeans. For example, the disk may be stabilized in the lumen of thecylindrical tube via frictional engagement between the disk and thetube, notches in the interior wall of the tube, a suitable adhesive, orone or more washers or other structural stabilizing members. In certainembodiments, the first wall structure, the one or more washers orstabilizing members, and/or the adhesive are made of silicone.

FIGS. 1-3 show an implantable drug delivery device 100 including ahousing 102 having a closed drug reservoir lumen bounded by a first wallstructure 104 and a hydrophilic second wall structure 106, and a drug108, in the form of a plurality of drug tablets, contained in the drugreservoir lumen, wherein the first wall structure 104 is impermeable tothe drug, and the second wall structure 106 is permeable to the drug.The second wall structure 106 is an end wall disposed at at least oneend of the first wall structure 104, which is a cylindrical tube. Thesecond wall structure 106 is in the form of a disk that is stabilized ina lumen of the cylindrical tube 104. As shown in FIG. 1, the disk 106may be friction fit or adhered to the lumen of the cylindrical tube 104.As shown in FIG. 2, outer washer 110 is adjacent to disk 106 andstabilizes it within the lumen of the cylindrical tube 104. As shown inFIG. 3, outer washer 110 and inner washer 112 may sandwich disk 106 andstabilize it within the lumen of the cylindrical tube 104. As shown inFIG. 3, the drug tablets 109 adjacent the inner washer 112 may have adecreased tablet diameter relative to the other drug tablets 108, so asto fit within the inner diameter of the inner washer 112. The drugtablets 109 may be skipped and in such case, there will be a void spacein the inner washer 112, which may create induction or lag time beforedrug release starts. Depending on the void space in the inner washer112, the lag time can be varied or controlled.

The disk-stabilizing washer component can take a variety of forms.Non-limiting examples are shown in FIGS. 4A-7. As shown in FIGS. 4A-4D,inner and outer washers 412, 410 may sandwich disk 406. The drug tablet409 adjacent the inner washer 412 may have a decreased tablet diameterrelative to the other drug tablets 408, so as to fit within the innerdiameter of the inner washer 412. The washers 410, 412, the disk 406,and the drug tablets 408, 409 may then be disposed within a cylindricaltube (i.e., the first wall structure). For example, the inner and outerwashers may be made of silicone, and the hydrophilic disk may beTecophilic™. In one embodiment, the washers have an inner diameter of2.16 mm and an outer diameter of 2.77 mm, and the drug tablets havediameters of 2.16 mm and 2.64 mm. In certain embodiments, as shown inFIGS. 4A-4C, the washers 410, 412 include one or more grooves 413 toreceive an adhesive (e.g., room temperature vulcanizing (RTV) silicone).In one embodiment, the grooves have a diameter of 0.3 mm. For example,the adhesive may be applied at one or both of the inner and outerwashers. The inner surface of outer washer 410 may be covered withhydrophilic material to aid the initial wetting of such surface once incontact with water or bodily fluid. For example, the inner surface ofthe outer washer may be covered with water soluble excipients, such assodium chloride, urea, polyvinylpyrrolidone (PVP), or polyethyleneglycol (PEG), either in a powder form or a tablet form, which may fitthe void space in the outer washer. In addition, the inner surface ofthe outer washer can be coated with hydrophilic polymers used toconstruct the second wall structure. Appropriate hydrophilic coatingmethod varies depending on the substrate condition of the inner surfaceof the outer washer.

As shown in FIG. 5, in one embodiment, the first wall structure 504 is acylindrical tube having an inner diameter at the end of the tube that issmaller than the inner diameter of the remainder of the tube. As shownin FIG. 5, the inner diameter of the end of the cylindrical tube 504 maybe smaller than the diameter of the disk 506, such that the end of thecylindrical tube 504 stabilizes the disk 506 on one side. Inner washer512 may be used to stabilize the disk 506 on the other side.

As shown in FIG. 6, in one embodiment, the first wall structure is acylindrical tube 604 having a housing insert 620. The housing insert 620is fixed in the cylindrical tube 604 to stabilize the disk 606 from oneside. As shown in FIG. 6, the housing insert 620 may be cylindrical inshape and have an outer diameter such that the insert 620 may be securedwithin the cylindrical tube 604. The inner diameter of an end of thecylindrical housing insert 620 may be smaller than the diameter of thedisk 606, such that the end of the insert 620 stabilizes the disk 606 onone side. Outer washer 610 may be disposed within the housing insert 620to stabilize the disk 606 on the other side. Drug tablets 608 may beprovided in the lumen of the cylindrical tube 604.

FIG. 7 illustrates another embodiment of a device having a housinginsert 720. Housing insert 720 is fixed in cylindrical tube 704 tostabilize the disk 706 from one side. Inner washer 712 stabilizes thedisk 706 from the other side. Drug tablets 708 are provide in the lumenof the cylindrical tube 704 and insert 720.

FIG. 8 illustrates one embodiment of a drug delivery device 800 having awasher-stabilized disk 806 at each end of the device. The disks 806 arestabilized between inner washers 812 and outer washers 810. Drug tabletsare provided within the lumen of cylindrical tube 804, with the drugtablets 809 adjacent to the disks 806 having a smaller diameter thantablets 808.

Thus, the assembly of a device in which a closed housing is formed by acylindrical tube first wall structure and an end wall second wallstructure, may take many forms. Given a specific drug formulation, thefollowing parameters may be tailored to affect the release profile ofthe drug: disk material, thickness, and diameter; inner washer innerdiameter, outer diameter, and length; outer washer inner diameter, outerdiameter, and length; initial void space in the inner washer (e.g., alarger void may result in a longer release lag time). For example, theinner washer and the outer washer may be fixed in a silicone tube sothat the disk is stabilized in both longitudinal directions. In oneembodiment, the washers are made of a high durometer silicone (e.g.,MED-4780 by Nusil Technology LLC) and a silicone adhesive (e.g.,MED3-4213 by Nusil Technology LLC) is applied at the interface betweenthe washer and tube.

The hydrophilic polymer wall structure tends to absorb water and swell,and the degree of swelling depends on water absorption behavior of thepolymer. Therefore, disk wall thickness can be selected based on thetype of hydrophilic polymer used and its degree of water absorption, toachieve a desired drug release rate. Initial void space in the innerwasher can also be used to program a lag time in the drug releaseprofile. Overall, to decrease the release rate of a drug through a disk,the disk diameter, inner washer inner diameter, and outer washer innerdiameter may be decreased, and the length(s) of the outer and/or innerwashers, and the disk thickness may be increased.

In other embodiments, as shown in FIGS. 9-12C, the first wall structureand the second wall structure are adjacent one another and together forma cylindrical tube. For example, such devices may be formed in acoextrusion process. In one embodiment, the coextruded first and secondwall structures are thermoplastic polymers possessing the desiredproperties.

As shown in FIG. 9, the first wall structure 904 and second wallstructure 906 together form a cylindrical tube having a lumen in whichdrug formulation 908 is contained. The second wall structure 906 is inthe form of a strip extending along at least a portion of the length ofthe first wall structure 904 and is permeable to the drug, while thefirst wall structure 904 is not permeable to the drug. In certainembodiments, multiple hydrophilic strips or regions may be used in asingle device.

FIGS. 10A-10C illustrate another embodiment of a device in which thefirst wall structure 1004 forms a closed cylindrical tube with secondwall structure 1006. In FIGS. 10A-10C, first wall structure 1004 is inthe form of a tube having an aperture in a sidewall thereof. Hydrophilicband 1006 is sized and shaped to fit within sleeve 1005, which has anaperture similarly sized to that of the first wall structure 1004.Hydrophilic band 1006 is disposed around tube 1004 such that thehydrophilic material covers the aperture in the tube 1004, therebyforming a closed cylindrical tube therewith. Sleeve 1005 may be disposedover the band 1006 to stabilize the band 1006, while exposing the band1006 by aligning the aperture of the sleeve 1005 with the aperture ofthe first wall structure 1004 to allow release of the drug. For example,an adhesive may be applied to the lumen of the sleeve to adhere thesleeve and band assembly to the first wall structure. As shown in FIG.10C, the inner diameter of the hydrophilic second wall band 1006 may beflush with the inner diameter of the sleeve 1005, which has a notchtherein to accommodate the band 1006. In certain embodiments, the firstwall structure tube, the sleeve, and/or the adhesive are made ofsilicone, while the hydrophilic band is made of a thermoplasticpolyurethane, such as Tecophilic™.

FIGS. 11A-11B illustrate another embodiment of a device in which thefirst wall structure 1104 forms a closed cylindrical tube with secondwall structure 1106. First wall structure 1104 is in the form of a tubehaving three apertures in a sidewall thereof. Hydrophilic second wallstructure 1106 is in the form of a tube containing drug tablets 1108.Hydrophilic tube 1106 is sized and shaped to fit within the first wallstructure tube 1104, such that the hydrophilic material of the tube 1106is disposed at each of the apertures of the first wall structure 1104,thereby forming a closed cylindrical tube therewith. For example, thefirst wall structure tube may have one or more apertures therein. Incertain embodiments, the first wall structure has one, two, three, ormore apertures therein.

FIGS. 12A-12C illustrate another embodiment of a device in which thefirst wall structure 1204 forms a closed cylindrical tube withhydrophilic second wall structure 1206. First wall structure 1204 is inthe form of a tube having three apertures in a sidewall thereof.Hydrophilic second wall structure 1206 is a semi-cylindrical insert thatis sized and shaped to fit within the tube 1204, such that hydrophilicsecond wall 1206 is disposed at each of the apertures of the tube 1204,thereby forming a closed cylindrical tube therewith. The hydrophilicsecond wall structure may take the form of a thin strip that is sized toextend along only the circumference of the tube containing theapertures. Alternatively, the hydrophilic second wall structure mayextend from about 50 percent to about 100 percent of the circumferenceof the tube containing the apertures. In certain embodiments, the tubeis silicone while the hydrophilic insert structure is a thermoplasticpolyurethane, such as Tecophilic™.

Thus, the size, shape, thickness, and material properties of the secondwall structure may be selected to achieve a desired drug release rate.Moreover, in the embodiments utilizing an aperture-exposed second wallstructure, the size and number of the aperture(s) may also be selectedto achieve a desired drug release rate.

In embodiments in which the first and second wall structures togetherform a cylindrical tube, any suitable end plugs or closures may be usedto seal the ends of the tube after the drug is loaded. These endplugs/closures ensure that the hydrophilic polymer portions exposed atthe external surface of the tube (e.g., by forming a portion of theexternal tube or by being exposed via apertures in the external tube)are the only path for drug release. In embodiments in which the secondwall structure forms an end wall of the tube, no end plug or closure ispresent at the end(s) which include the second wall structure(s). Thatis, in embodiments in which the second wall structure forms an end ofthe device, no end cap or closure is used, so that the second wallstructure is unobstructed to provide a path for drug release.

In a preferred embodiment, the device is configured to release atherapeutically effective amount of the drug, where the rate of therelease of the drug from the drug delivery device is zero order over atleast 36 hours. In one embodiment, the rate of the release of the drugfrom the drug delivery device is essentially zero order over at least 7days. In certain embodiments, the device is configured to begin releaseof the drug after a lag time, for example due to a void space in theinner washer. In certain embodiments, the lag time may at least about 30minutes, from about 12 hours to about 24 hours, or up to about 2 days.

In preferred embodiments, the drugs are gemcitabine hydrochloride andtrospium chloride. In one embodiment, at least 25 mg/day of gemcitabineis released over 7 days. In another embodiment, at least 1 mg/day oftrospium chloride is released over 7 days to 3 months. In otherembodiments, other drugs can be delivered with the devices describedherein.

Other Aspects of the Implantable Drug Delivery Device

The devices and methods disclosed herein build upon those described inU.S. Pat. Nos. 8,182,464 and 8,343,516, as well as in U.S. ApplicationPublication No. 2009/0149833 (MIT 12988); U.S. Application PublicationNo. 2010/0331770 (TB 101); U.S. Application Publication No. 2010/0060309(TB 108); U.S. Application Publication No. 2011/0202036 (TB 107); U.S.Application Publication No. 2011/0152839 (TB 112); PCT/US11/46843, filedAug. 5, 2011 (TB 113); U.S. application Ser. No. 13/267,560, filed Oct.6, 2011 (TB 116); U.S. application Ser. No. 13/267,469, filed Oct. 6,2011 (TB 117); and U.S. application Ser. No. 13/347,513, filed Jan. 10,2012 (TB 120), each of which is incorporated herein by reference.

In certain embodiments, the devices are configured for intravesicalinsertion and retention in a patient. For example, the devices can beelastically deformable between a relatively straightened shape suitedfor insertion through a lumen into a body cavity of a patient and aretention shape suited to retain the device within the body cavity, suchas shown in FIG. 8A. When in the retention shape after deployment in thebladder, for example, the devices may resist excretion in response tothe forces of urination or other forces. Since the devices are designedto be retained within a lumen or body cavity, they are capable ofovercoming some of the deficiencies of conventional treatments, such asthose related to the bladder. The devices described herein can beinserted once and release drug over a desired period of time withoutsurgery or frequent interventions. The devices, as a result, may reducethe opportunity for infection and side effects, increase the amount ofdrug delivered locally or regionally to the bladder, or improve thequality of life of the patient during the treatment process. After drugrelease, the devices can be removed, for example by cystoscope andforceps, or be bioerodible, at least in part, to avoid a retrievalprocedure.

The device may be loaded with at least one drug in the form of one ormore solid drug units, such as tablets, capsules, or pellets. Providingone or more drugs in solid form to a patient is often advantageous.Solid drugs can provide a relatively large drug payload volume to totaldevice volume and potentially enhance stability of the drugs duringshipping, storage, before use, or before drug release. Solid drugs,however, should be solubilizable in vivo in order to diffuse intothrough the drug-permeable component and into the patient's surroundingtissues in a therapeutically effective amount.

Each drug reservoir lumen may hold one or several drug tablets or othersolid drug units. In one embodiment, the device holds from about 10 to100 cylindrical drug tablets, such as mini-tablets, among a number ofdiscrete drug reservoir lumens. In certain embodiments, the mini-tabletsmay each have a diameter of about 1.0 to about 3.3 mm, such as about 1.5to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, such asabout 2.0 to about 4.5 mm.

The devices may be inserted into a patient using a cystoscope orcatheter. Typically, a cystoscope for an adult human has an outerdiameter of about 5 mm and a working channel having an inner diameter ofabout 2.4 mm to about 2.6 mm. In embodiments, a cystoscope may have aworking channel with a larger inner diameter, such as an inner diameterof 4 mm or more. Thus, the device may be relatively small in size. Forexample, when the device is elastically deformed to the relativelystraightened shape, the device for an adult patient may have a totalouter diameter that is less than about 2.6 mm, such as between about 2.0mm and about 2.4 mm. For pediatric patients, the dimensions of thedevice are anticipated to be smaller, e.g., proportional for examplebased on the anatomical size differences and/or on the drug dosagedifferences between the adult and pediatric patients. In addition topermitting insertion, the relatively small size of the device may alsoreduce patient discomfort and trauma to the bladder.

In one embodiment, the overall configuration of the device promotes invivo tolerability for most patients. In a particular embodiment, thedevice is configured for tolerability based on bladder characteristicsand design considerations described in U.S. Application Publication No.2011/0152839 (TB 112), which is incorporated herein by reference.

Within the three-dimensional space occupied by the device in theretention shape, the maximum dimension of the device in any directionpreferably is less than 10 cm, the approximate diameter of the bladderwhen filled. In some embodiments, the maximum dimension of the device inany direction may be less than about 9 cm, such as about 8 cm, 7 cm, 6cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 or smaller. In particularembodiments, the maximum dimension of the device in any direction isless than about 7 cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3cm, 2.5 cm or smaller. In preferred embodiments, the maximum dimensionof the device in any direction is less than about 6 cm, such as about 5cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or smaller. More particularly,the three-dimension space occupied by the device is defined by threeperpendicular directions. Along one of these directions the device hasits maximum dimension, and along the two other directions the device mayhave smaller dimensions. For example, the smaller dimensions in the twoother directions may be less than about 4 cm, such as about 3.5 cm, 3cm, 2.5 cm or less. In a preferred embodiment, the device has adimension in at least one of these directions that is less than 3 cm.

In some embodiments, the device may have a different dimension in atleast two of the three directions, and in some cases in each of thethree directions, so that the device is non-uniform in shape. Due to thenon-uniform shape, the device may be able to achieve an orientation ofreduced compression in the empty bladder, which also is non-uniform inshape. In other words, a particular orientation of the device in theempty bladder may allow the device to exert less contact pressureagainst the bladder wall, making the device more tolerable for thepatient.

The overall shape of the device may enable the device to reorient itselfwithin the bladder to reduce its engagement or contact with the bladderwall. For example, the overall exterior shape of the device may becurved, and all or a majority of the exterior or exposed surfaces of thedevice may be substantially rounded. The device also may besubstantially devoid of sharp edges, and is exterior surfaces may beformed from a material that experiences reduced frictional engagementwith the bladder wall. Such a configuration may enable the device toreposition itself within the empty bladder so that the device applieslower contact pressures to the bladder wall. In other words, the devicemay slip or roll against the bladder wall into a lower energy position,meaning a position in which the device experiences less compression.

In one embodiment, device is generally planar in shape even though thedevice occupies three-dimensional space. Such a device may define aminor axis, about which the device is substantially symmetrical, and amajor axis that is substantially perpendicular to the minor axis. Thedevice may have a maximum dimension in the direction of the major axisthat does not exceed about 6 cm, and in particular embodiments is lessthan 5 cm, such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm,or smaller. The device may have a maximum dimension in the direction ofthe minor axis that does not exceed about 4.5 cm, and in particularembodiments is less than 4 cm, such as about 3.5 cm, about 3 cm, orsmaller. The device is curved about substantially its entire exteriorperimeter in both a major cross-sectional plane and a minorcross-sectional plane. In other words, the overall exterior shape of thedevice is curved and the cross-sectional shape of the device is rounded.Thus, the device is substantially devoid of edges, except for edges onthe two flat ends, which are completely protected within the interior ofthe device when the device lies in a plane. These characteristics enablethe device to reorient itself into a position of reduced compressionwhen in the empty bladder.

The device also may be small enough in the retention shape to permitintravesical mobility. In particular, the device when deployed may besmall enough to move within the bladder, such as to move freely orunimpeded throughout the entire bladder under most conditions of bladderfullness, facilitating patient tolerance of the device. Free movement ofthe device also facilitates uniform drug delivery throughout the entirebladder.

The device also may be configured to facilitate buoyancy, such as withthe use of low density materials of construction for the housingcomponents and/or by incorporating gas or gas generating materials intothe housing, as described for example in U.S. Application PublicationNo. 2012/0089121 (TB 116), which is incorporated herein by reference. Ingeneral, the device in the dry and drug-loaded state may have a densityin the range of about 0.5 g/mL to about 1.5 g/mL, such as between about0.7 g/mL to about 1.3 g/mL. In some embodiments, the device in the dryand drug-loaded state has a density that is less than 1 g/mL.

The implantable drug delivery device can be made to be completely orpartially bioerodible so that no explantation, or retrieval, of thedevice is required following release of the drug formulation. In someembodiments, the device is partially bioerodible so that the device,upon partial erosion, breaks into non-erodible pieces small enough to beexcreted from the bladder. As used herein, the term “bioerodible” meansthat the device, or part thereof, degrades in vivo by dissolution,enzymatic hydrolysis, erosion, resorption, or combinations thereof. Inone embodiment, this degradation occurs at a time that does notinterfere with the intended kinetics of release of the drug from thedevice. For example, substantial erosion of the device may not occuruntil after the drug formulation is substantially or completelyreleased. In another embodiment, the device is erodible and the releaseof the drug formulation is controlled at least in part by thedegradation or erosion characteristics of the erodible device body. Thedevices described herein may be designed to conform with thecharacteristics of those described in U.S. Application Publication No.2012/0089122 (TB 117), which is incorporated herein by reference.

Useful biocompatible erodible materials of construction are known in theart. Examples of suitable such materials include synthetic polymersselected from poly(amides), poly(esters), poly(ester amides),poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo poly(aminoacids), poly(glycerol-sebacate)(PGS), copolymers thereof, and mixturesthereof. In one embodiment, the resorbable synthetic polymers areselected from poly(lactic acids), poly(glycolic acids),poly(lactic-co-glycolic acids), poly(caprolactones), and mixturesthereof. Other curable bioresorbable elastomers includepoly(caprolactone) (PC) derivatives, amino alcohol-based poly(esteramides) (PEA) and poly (octane-diol citrate) (POC). PC-based polymersmay require additional cross-linking agents such as lysine diisocyanateor 2,2-bis(8-caprolacton-4-yl)propane to obtain elastomeric properties.

Alternatively, the implantable drug delivery device may be at leastpartially non-bioerodible. It may be formed of medical grade siliconetubing, as known in the art. Other examples of suitable non-resorbablematerials include synthetic polymers selected from ethylene vinylacetate (EVA), poly(ethers), poly(acrylates), poly(methacrylates),poly(vinyl pyrolidones), poly(vinyl acetates), poly(urethanes),celluloses, cellulose acetates, poly(siloxanes), poly(ethylene),poly(tetrafluoroethylene), polyamide and other fluorinated polymers,poly(siloxanes), copolymers thereof, and combinations thereof. Followingrelease of the drug formulation, the device and/or the retention framemay be removed substantially intact or in multiple pieces.

The drug delivery device may be sterilized before being inserted into apatient. In one embodiment, the device is sterilized using a suitableprocess such as gamma irradiation or ethylene oxide sterilization,although other sterilization processes may be used.

Retention of the Device in a Body Cavity

The devices described herein are elastically deformable between arelatively straightened shape suited for insertion through a lumen intothe bladder (or other body cavity) of a patient and a retention shapesuited to retain the device within the bladder (or other body cavity).In certain embodiments, the drug delivery device may naturally assumethe retention shape and may be deformed, either manually or with the aidof an external apparatus, into the relatively straightened shape forinsertion into the body. Once deployed the device may spontaneously ornaturally return to the initial, retention shape for retention in thebody.

For the purposes of this disclosure, the term “retention shape”generally denotes any shape suited for retaining the device in theintended implantation location, including, but not limited to, a coiledor “pretzel” shape, such as shown in FIG. 8A, which is suited forretaining the device in the bladder. Similarly, the term “relativelystraightened shape” generally denotes any shape suited for deploying thedrug delivery device into the body, including, but not limited to, alinear or elongated shape, which is suited for deploying the devicethrough the working channel of catheter, cystoscope, or other deploymentinstrument positioned in a lumen of the body, such as the urethra.

In some embodiments, the drug delivery devices do not need a retentionframe to be elastically deformable between a relatively straightenedshape and a retention shape. In these embodiments, the material fromwhich the housing is formed makes the device capable of beingelastically deformed between the two shapes.

In other embodiments, the drug delivery devices include a retentionframe that is associated with the housing. The properties of theretention frame cause the device to function as a spring, deforming inresponse to a compressive load but spontaneously returning to itsinitial shape once the load is removed.

As shown in FIGS. 8A-8B, 9, 11A-11B, and 12A-12C, the housing mayinclude one or more retention frame lumens 822, 922, 1122, and 1222,respectively, through which at least a portion of a retention frame 824,924, 1124, 1224, respectively, is threaded. In some embodiments, thehousing does not include a separate retention frame lumen, and theretention frame is affixed to the housing any other means, such as anadhesive, or the retention frame and drug occupy the same lumen.

In certain embodiments, the retention frame, like the devicesthemselves, may naturally assume the retention shape, may be deformedinto the relatively straightened shape, and may spontaneously return tothe retention shape upon insertion into the body. The retention frame inthe retention shape may be shaped for retention in a body cavity, andthe retention frame in the relatively straightened shape may be shapedfor insertion into the body through the working channel of a deploymentinstrument such as a catheter or cystoscope. To achieve such a result,the retention frame may have an elastic limit, modulus, and/or springconstant selected to impede the device from assuming the relativelylower-profile shape once implanted. Such a configuration may limit orprevent accidental expulsion of the device from the body under expectedforces. For example, the device may be retained in the bladder duringurination or contraction of the detrusor muscle.

In a preferred embodiment, the device is elastically deformable betweena relatively straightened shape suited for insertion through a catheteror cystoscope extending through a patient's urethra of a patient and acurved or coiled shape suited to retain the device within the bladder(i.e., to prevent its expulsion from the bladder during urination)following release of the device from the end of the catheter orcystoscope. In a particular configuration of this embodiment, the devicehas an elastic wire or strip serving as the retention frame, and theelastic wire or strip acts as a spring to maintain the device in thecurved or coiled shape in the absence of a compressive load on thedevice and when the device is under compression from the bladder wallsduring urination or other contraction of the patient's detrusor muscle.

In certain embodiments, the retention frame includes or consists of anelastic wire or an elastic strip. In one embodiment, the elastic wiremay comprise a biocompatible shape-memory material or a biodegradableshape memory polymer as known in the art. The elastic wire also mayinclude a relatively low modulus elastomer, which may be relatively lesslikely to irritate or cause ulcer within the bladder or otherimplantation site and may be biodegradable so that the device need notbe removed. Examples of low modulus elastomers include polyurethane,silicone, styrenic thermoplastic elastomer, and poly(glycerol-sebacate)(PGS). The elastic wire may be coated with a biocompatible polymer, suchas a coating formed from one or more of silicone, polyurethane, styrenicthermoplastic elastomer, Silitek, Tecoflex, C-flex, and Percuflex.

In some embodiments, the retention frame lumen may include the retentionframe and a filling material, such as a silicone adhesive, such asMED3-4213 by Nusil Technology LLC, although other filling materials maybe used. The filling material is optional and may be omitted; however,its inclusion may fill the void in the retention frame lumen about theretention frame and may reduce the tendency of the drug reservoir lumento stretch along, or twist or rotate about, the retention frame, whilemaintaining the drug reservoir lumen in a selected orientation withreference to the retention frame.

A retention frame that assumes a pretzel shape may be relativelyresistant to compressive forces. The pretzel shape essentially comprisestwo sub-circles, each having its own smaller arch and sharing a commonlarger arch. When the pretzel shape is first compressed, the larger archabsorbs the majority of the compressive force and begins deforming, butwith continued compression the smaller arches overlap, and subsequently,all three of the arches resist the compressive force. The resistance tocompression of the device as a whole increases once the two sub-circlesoverlap, impeding collapse and voiding of the device as the bladdercontracts during urination.

In embodiments in which the retention frame (or the housing itself inembodiments without a retention frame) comprises a shape-memorymaterial, the material used to form the frame may “memorize” andspontaneously assume the retention shape upon the application of heat tothe device, such as when exposed to body temperatures upon entering thebladder. The windings, coils, or spirals of the frame may have a numberof configurations. For example, the frame may be in a curl configurationcomprising one or more loops, curls or sub-circles. The ends of theelastic wire may be adapted to avoid tissue irritation and scarring,such as by being soft, blunt, inwardly directed, joined together, or acombination thereof.

The retention frame may have a two-dimensional structure that isconfined to a plane, a three-dimensional structure, such as a structurethat occupies the interior of a spheroid, or some combination thereof.The frames may comprise one or more loops, curls, or sub-circles,connected either linearly or radially, turning in the same or inalternating directions, and overlapping or not overlapping. The framesmay comprise one or more circles or ovals arranged in a two-dimensionalor a three-dimensional configuration, the circles or ovals may be eitherclosed or opened, having the same or different sizes, overlapping or notoverlapping, and joined together at one or more connecting points. Theretention frame portion also may be a three-dimensional structure thatis shaped to occupy or wind about a spheroid-shaped space, such as aspherical space, a space having a prorate spheroid shape, or a spacehaving an oblate spheroid shape. Retention frame portions may be shapedto occupy or wind about a spherical space. The retention frame portionmay generally take the shape of two intersecting circles lying indifferent planes, two intersecting circles lying in different planeswith inwardly curled ends, three intersecting circles lying in differentplanes, or a spherical spiral. In each of these examples, the retentionframe portion can be stretched to the linear shape for deploymentthrough a deployment instrument. The retention frame portion may windabout or through the spherical space, or other spheroid-shaped space, ina variety of other manners. One or both of the retention frame andretention frame lumen may be omitted, in which case the housing itselfmay assume or may be deformed into any retention shape described herein.Examples of alternative configurations are described in the U.S. patentapplications incorporated by reference herein.

The Drug Formulation and Solid Drug Tablets

Generally, a drug formulation is formed into solid drug units that areloaded into the device housing. Each of the solid drug units is a solid,discrete object that substantially retains a selectively imparted shape(at the temperature and pressure conditions to which the delivery devicenormally will be exposed during assembly, storage, and handling beforeimplantation). The drug units may be in the form of tablets, capsules,pellets, or beads, although other configurations are possible.

The solid drug units can be formed using a stable and scalablemanufacturing process. Particularly, the drug tablets are sized andshaped for loading into and efficiently storing the tablets in a housingof a drug delivery device that can be deployed into the bladder oranother cavity, lumen, or tissue site in a patient in a minimallyinvasive manner.

The solid drug units may be made by a direct powder compaction ortabletting process, a molding process, or other processes known in thepharmaceutical arts. Suitable drug tablet forming methods are describedin U.S. Application Publication No. 2010/0330149 (TB 102), which isincorporated herein by reference. The drug formulation also may beloaded into the device housing in workable form and may cure therein.For example, in embodiments in which the drug formulation is configuredto be melted and solidified, the drug formulation can be melted,injected into the device housing in melted form and then solidified. Thedrug formulation also may be extruded with the device housing, may curewithin the housing, and subsequently may be cut in spaced positionsalong the length of the housing to form segments with exposed surfaceareas of drug.

The solid drug unit includes a drug formulation, which includes a drugcontent and may include an excipient content. In a preferred embodiment,the drug content includes one or more drugs, or active pharmaceuticalingredients (API), while the excipient content includes one or morepharmaceutically acceptable excipients. The drug formulation can includeessentially any therapeutic, prophylactic, or diagnostic agent, such asone that would be useful to deliver locally to a body cavity or lumen orregionally about the body cavity or lumen. The drug formulation mayconsist only of the API, or one or more excipients may be included. Asused herein, the term “drug” with reference to any specific drugdescribed herein includes its alternative forms, such as salt forms,free acid forms, free base forms, and hydrates. The term “excipient” isknown in the art, and representative examples of excipients useful inthe present drug units may include ingredients such as binders,lubricants, glidants, disintegrants, colors, fillers, diluents,coatings, or preservatives, as well as other non-active ingredients tofacilitate manufacturing, stability, dispersibility, wettability, and/orrelease kinetics of the drug or administering the drug unit. The drugmay be small molecule, macromolecule, biologic, or metabolite, amongother forms/types of active ingredients.

In order to maximize the amount of drug that can be stored in andreleased from a given drug delivery device of a selected (small) size,the drug unit preferably comprises a high weight fraction of drug orAPI, with a reduced or low weight fraction of excipients as are requiredfor solid drug unit manufacturing and device assembly and useconsiderations. For the purposes of this disclosure, terms such as“weight fraction,” “weight percentage,” and “percentage by weight” withreference to drug, or API, refers to the drug or API in the formemployed, such as in salt form, free acid form, free base form, orhydrate form. For example, a solid drug unit that has 90% by weight of adrug in salt form may include less than 90% by weight of that drug infree base form.

In one embodiment, the solid drug unit is more than 50% by weight drug.In another embodiment, 75% or more of the weight of the solid drug unitis drug, with the remainder of the weight comprising excipients, such aslubricants and binders that facilitate making the solid drug unit. Forthe purposes of this disclosure, the term “high weight fraction” withreference to the drug or API means that excipients constitute less than25 wt %, preferably less than 20 wt %, more preferably less than 15 wt%, and even more preferably less than 10 wt % of the solid drug unit. Insome cases, the drug content comprises about 75% or more of the weightof the solid drug unit. More particularly, the drug content may compriseabout 80% or more of the weight of the drug tablet. For example, thedrug content may comprise between about 85% and about 99.9% of theweight of the solid drug unit. In some embodiments, the excipientcontent can be omitted completely.

In one embodiment, the drug and excipients are selected and the soliddrug unit formulated to be water soluble, so that the solid drug unitscan be solubilized when the device is located within the bladder, torelease the solubilized drug.

The individual solid drug units may have essentially any selected shapeand dimension that fits within the devices described herein. In oneembodiment, the solid drug units are sized and shaped such that the drugreservoir lumens in the housings are substantially filled by a selectnumber of solid drug units. Each solid drug unit may have across-sectional shape that substantially corresponds to across-sectional shape of the drug reservoir lumen of a particularhousing. For example, the drug units may be substantially cylindrical inshape for positioning in a substantially cylindrical drug reservoirlumen. Once loaded, the solid drug units can, in some embodiments,substantially fill the drug reservoir lumens, forming the drug housingportion.

In one embodiment, the solid drug units are shaped to align in a rowwhen the device is in its deployment configuration. For example, eachsolid drug unit may have a cross-sectional shape that corresponds to thecross-sectional shape of the drug reservoir lumens in the housing, andeach solid drug unit may have end face shapes that correspond to the endfaces of adjacent solid drug units. The interstices or breaks betweensolid drug units can accommodate deformation or movement of the device,such as during deployment, while permitting the individual drug units toretain their solid form. Thus, the drug delivery device may berelatively flexible or deformable despite being loaded with a soliddrug, as each drug unit may be permitted to move with reference toadjacent drug units.

In embodiments in which the solid drug units are designed for insertionor implantation in a lumen or cavity in the body, such as the bladder,via a drug delivery device, the drug units may be “mini-tablets” thatare suitably sized and shaped for insertion through a natural lumen ofthe body, such as the urethra. For the purpose of this disclosure, theterm “mini-tablet” generally indicates a solid drug unit that issubstantially cylindrical in shape, having end faces and a side facethat is substantially cylindrical. The mini-tablet has a diameter,extending along the end face, in the range of about 1.0 to about 3.2 mm,such as between about 1.5 and about 3.1 mm. The mini-tablet has alength, extending along the side face, in the range of about 1.7 mm toabout 4.8 mm, such as between about 2.0 mm and about 4.5 mm. Thefriability of the tablet may be less than about 2%. Embodiments of soliddrug units and systems and methods of making the same are furtherdescribed below with reference to U.S. patent applications incorporatedby reference herein.

In one embodiment, the drug formulation is in a solid form. In anotherembodiment, the drug formulation is in semi-solid form, such as anemulsion or suspension; a gel or a paste. For example, the drugformulation may be a highly viscous emulsion or suspension. As usedherein, the solid form includes semi-solid forms unless otherwiseindicated. In one embodiment, the drug formulation is in a liquid form.

The drug may be a low solubility drug. As used herein, the term “lowsolubility” refers to a drug having a solubility from about 0.01 mg/mLto about 10 mg/mL water at 37° C. In other embodiments, the drug is ahigh solubility drug. As used herein, the term “high solubility” refersto a drug having a solubility above about 10 mg/mL water at 37° C. Forexample, the approximate solubilities of certain drug formulations are:trospium chloride: 500 mg/mL; lidocaine HCl: 680 mg/mL; lidocaine base:8 mg/mL, gemcitabine HCl: 80 mg/mL; gemcitabine base: 15 mg/mL;oxybutynin HCl: 50 mg/mL; oxybutynin base: 0.012 mg/mL; and tolterodinetartrate: 12 mg/mL.

In one embodiment, the drug delivery device is used to treat renal orurinary tract cancer, such as bladder cancer and prostate cancer. Drugsthat may be used include antiproliferative agents, cytotoxic agents,chemotherapeutic agents, or combinations thereof. Representativeexamples of drugs which may be suitable for the treatment of urinarytract cancer include Bacillus Calmette Guerin (BCG) vaccine, docetaxel,cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cellwall-DNA complex (MCC), methotrexate, vinblastine, thiotepa, mitomycin(e.g., mitomycin C), fluorouracil, leuprolide, diethylstilbestrol,estramustine, megestrol acetate, cyproterone, flutamide, a selectiveestrogen receptor modulators (i.e. a SERM, such as tamoxifen), botulinumtoxins, and cyclophosphamide. The drug may comprise a monoclonalantibody, a TNF inhibitor, an anti-leukin, or the like. The drug alsomay be an immunomodulator, such as a TLR agonist, including imiquimod oranother TLR7 agonist. The drug also may be a kinase inhibitor, such as afibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinaseinhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or amitogen-activated protein kinase (MAPK) inhibitor, among others orcombinations thereof. Other examples include celecoxib, erolotinib,gefitinib, paclitaxel, polyphenon E, valrubicin, neocarzinostatin,apaziquone, Belinostat, Ingenol mebutate, Urocidin (MCC), Proxinium (VB4845), BC 819 (BioCancell Therapeutics), Keyhole limpet haemocyanin, LOR2040 (Lorus Therapeutics), urocanic acid, OGX 427 (OncoGenex), and SCH721015 (Schering-Plough). The drug treatment may be coupled with aconventional radiation or surgical therapy targeted to the canceroustissue.

In one embodiment, the devices described herein are loaded with ananesthetic agent, analgesic agent, and combinations thereof. Theanesthetic agent may be an aminoamide, an aminoester, or combinationsthereof. Representative examples of aminoamides or amide-classanesthetics include articaine, bupivacaine, carticaine, cinchocaine,etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocalne,ropivacaine, and trimecaine. Representative examples of aminoesters orester-class anesthetics include amylocalne, benzocaine, butacaine,chloroprocaine, cocaine, cyclomethycaine, dimethocaine, hexylcaine,larocaine, meprylcaine, metabutoxycaine, orthocaine, piperocaine,procaine, proparacaine, propoxycaine, proxymetacaine, risocaine, andtetracaine. These anesthetics typically are weak bases and may beformulated as a salt, such as a hydrochloride salt, to render themwater-soluble, although the anesthetics also can be used in free base orhydrate form. Other anesthetics, such as lontocaine, also may be used.The drug also can be an antimuscarinic compound that exhibits ananesthetic effect, such as oxybutynin or propiverine. The drug also mayinclude other drugs described herein, alone or in combination with alocal anesthetic agent.

In certain embodiments, the analgesic agent includes an opioid.Representative examples of opioid agonists include alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone,papavereturn, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, proheptazine, promedol,properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol,pharmaceutically acceptable salts thereof, and mixtures thereof. Otheropioid drugs, such as mu, kappa, delta, and nociception opioid receptoragonists, are contemplated.

Representative examples of other suitable pain relieving agents includesuch agents as salicyl alcohol, phenazopyridine hydrochloride,acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen,indomethacin, and naproxen.

In certain embodiments, the drug delivery device is used to treatinflammatory conditions such as interstitial cystitis, radiationcystitis, painful bladder syndrome, prostatitis, urethritis,post-surgical pain, and kidney stones. Non-limiting examples of specificdrugs for these conditions include lidocaine, glycosaminoglycans (e.g.,chondroitin sulfate, sulodexide), pentosan polysulfate sodium (PPS),dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate,ketorolac, cyclosporine, or combinations thereof. For kidney stones, thedrug(s) may be selected to treat pain and/or to promote dissolution ofrenal stones.

Other non-limiting examples of drugs that may be used in the treatmentof IC include nerve growth factor monoclonal antibody (MAB) antagonists,such as Tanezumab, and calcium channel alpha-2-delta modulators, such asPD-299685 or gabepentin. Evidence suggests that the bladder expressesnerve growth factor (NGF) locally, since exogenously delivered NGF intothe bladder induces bladder hyperactivity and increases the excitabilityof dissociated bladder afferent neurons (Nature Rev Neurosci 2008;9:453-66). Accordingly, it would be advantageous to locally deliver aMAB or other agent against NGF using the described delivery devices,significantly reducing the total dose needed for therapeutic efficacy.Evidence also suggests that binding of the alpha-2-delta unit ofvoltage-sensitive calcium channels, such as with gabapentin, may beeffective in the treatment of diseases of neuropathic pain such asfibromyalgia and that there may be common mechanisms between IC anddiseases of neuropathic pain (See Tech Urol. 2001 March, 7(1):47-49).Accordingly, it would be advantageous to locally deliver a calciumchannel alpha-2-delta modulator, such as PD-299685 or gabepentin, usingthe described delivery devices, minimizing does-related systemictoxicities in the treatment of IC.

Other intravesical cancer treatments include small molecules, such asApaziquone, adriamycin, AD-32, doxorubicin, doxetaxel, epirubicin,gemcitabine, HTI-286 (hemiasterlin analogue), idarubicin, γ-linolenicacid, mitozantrone, meglumine, and thiotepa; large molecules, such asEGF-dextran, HPC-doxorubicin, IL-12, IFN-a2b, IFN-γ, α-lactalbumin, p53adenovector, TNFα; combinations, such as Epirubicin+BCG,IFN+farmarubicin, Doxorubicin+5-FU (oral), BCG+IFN, and Pertussistoxin+cystectomy; activated cells, such as macrophages and T cells;intravesical infusions such as IL-2 and Doxorubicin; chemosensitizers,such as BCG+antifirinolytics (paramethylbenzoic acid or aminocaproicacid) and Doxorubicin+verapimil; diagnostic/imaging agents, such asHexylaminolevulinate, 5-aminolevulinic acid, Iododexyuridine, HMFG1Mab+Tc99m; and agents for the management of local toxicity, such asFormaline (hemorrhagic cystitis).

The drug delivery device can be used, for example, to treat urinaryincontinence, frequency, or urgency, including urge incontinence andneurogenic incontinence, as well as trigonitis. Drugs that may be usedinclude anticholinergic agents, antispasmodic agents, antimuscarinicagents, β-2 agonists, alpha adrenergics, anticonvulsants, norepinephrineuptake inhibitors, serotonin uptake inhibitors, calcium channelblockers, potassium channel openers, and muscle relaxants.Representative examples of suitable drugs for the treatment ofincontinence include oxybutynin, S-oxybutylin, emepronium, verapamil,imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine,clenbuterol, darifenacin, terodiline, trospium, hyoscyamin, propiverine,desmopressin, vamicamide, clidinium bromide, dicyclomine HCl,glycopyrrolate aminoalcohol ester, ipratropium bromide, mepenzolatebromide, methscopolamine bromide, scopolamine hydrobromide, iotropiumbromide, fesoterodine fumarate, YM-46303 (Yamanouchi Co., Japan),lanperisone (Nippon Kayaku Co., Japan), inaperisone, NS-21 (NipponShinyaku Orion, Formenti, Japan/Italy), NC-1800 (Nippon Chemiphar Co.,Japan), ZD-6169 (Zeneca Co., United Kingdom), and stilonium iodide.

In still another embodiment, the present intravesical drug deliverydevice is used to treat infections involving the bladder, the prostate,the kidney, and the urethra. Antibiotics, antibacterial, antifungal,antiprotozoal, antiseptic, antiviral and other antiinfective agents canbe administered for treatment of such infections. Representativeexamples of drugs for the treatment of infections include mitomycin,ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin,ampicillin, amoxicillin, nafcillin, trimethoprim, sulfonamidestrimethoprimsulfamethoxazole, erythromycin, doxycycline, metronidazole,tetracycline, kanamycin, penicillins, cephalosporins, andaminoglycosides.

In other embodiments, the drug delivery device is used to treat fibrosisof a genitourinary site, such as the bladder or uterus. Representativeexamples of drugs for the treatment of fibroids include pentoxphylline(xanthine analogue), antiTNF, antiTGF agents, GnRH analogues, exogenousprogestins, antiprogestins, selective estrogen receptor modulators,danazol and NSAIDs.

The implantable drug delivery device also may be used to treat spasticor flaccid neurogenic bladder. Representative examples of drugs for thetreatment of neurogenic bladder include analgesics or anaesthetics, suchas lidocaine, bupivacaine, mepivacaine, prilocalne, articaine, andropivacaine; anticholinergics; antimuscarinics such as oxybutynin orpropiverine; a vanilloid, such as capsaicin or resiniferatoxin;antimuscarinics such as ones that act on the M3 muscarinic acetylcholinereceptor (mAChRs); antispasmodics including GABA_(B) agonists such asbaclofen; botulinum toxins; capsaicins; alpha-adrenergic antagonists;anticonvulsants; serotonin reuptake inhibitors such as amitriptyline;and nerve growth factor antagonists. In various embodiments, the drugmay be one that acts on bladder afferents or one that acts on theefferent cholinergic transmission, as described in Reitz et al., SpinalCord 42:267-72 (2004).

In one embodiment, the drug is selected from those known for thetreatment of incontinence due to neurologic detrusor overactivity and/orlow compliant detrusor. Examples of these types of drugs include bladderrelaxant drugs (e.g., oxybutynin (antimuscarinic agent with a pronouncedmuscle relaxant activity and local anesthetic activity), propiverine,impratroprium, tiotropium, trospium, terodiline, tolterodine,propantheline, oxyphencyclimine, flavoxate, and tricyclicantidepressants); drugs for blocking nerves innervating the bladder andurethra (e.g., vanilloids (capsaicin, resiniferatoxin), botulinum-Atoxin); or drugs that modulate detrusor contraction strength,micturition reflex, detrusor sphincter dyssynergia (e.g., GABAb agonists(baclofen), benzodiazapines). In another embodiment, the drug isselected from those known for the treatment of incontinence due toneurologic sphincter deficiency. Examples of these drugs include alphaadrenergic agonists, estrogens, beta-adrenergic agonists, tricyclicantidepressants (imipramine, amitriptyline). In still anotherembodiment, the drug is selected from those known for facilitatingbladder emptying (e.g., alpha adrenergic antagonists (phentolamine) orcholinergics). In yet another embodiment, the drug is selected fromamong anticholinergic drugs (e.g., dicyclomine), calcium channelblockers (e.g., verapamil) tropane alkaloids (e.g., atropine,scopolamine), nociceptin/orphanin FQ, and bethanechol (e.g., m3muscarinc agonist, choline ester).

In certain embodiments, the drug is a steroid, such as triamcinolone,budesonide, or prednisolone.

In certain embodiments, the drug is lidocaine, gemcitabine, docetaxel,carboplatin, cisplatin, oxaliplatin, trospium, tolterodine, oxybutynin,or mitomycin C.

Other Device Features

The devices described herein may include a radio-opaque portion orstructure to facilitate detection or viewing (e.g., by X-ray imaging orfluoroscopy) of the device by a medical practitioner as part of theimplantation or retrieval procedure. In one embodiment, the housing isconstructed of a material that includes a radio-opaque filler material,such as barium sulfate or another radio-opaque material known in theart. Some housings may be made radio-opaque by blending radio-opaquefillers, such as barium sulfate or another suitable material, during theprocessing of the material from which the housing is formed. Theradio-opaque material may be associated with the retention frame inthose embodiments that include a retention frame. Ultrasound imaging orfluoroscopy may be used to image the device in vivo.

The housing of the implantable drug delivery device may further includea retrieval feature, such as a string, a loop, or other structure thatfacilitates removal of the device from the body cavity, for example forremoval of a non-resorbable device body following release of the drugformulation from the solid drug units. In one case, the device may beremoved from the bladder by engaging the string to pull the devicethrough the urethra. The device may be configured to assume a relativelynarrow or linear shape when pulling the device by the retrieval featureinto the lumen of a catheter or cystoscope or into the urethra.

Methods for Drug Delivery

The devices and methods disclosed herein may be adapted for use inhumans, whether male or female, adult or child, or for use in animals,such as for veterinary or livestock applications. Accordingly, the term“patient” may refer to a human or other mammalian subject.

In certain embodiments, a method of providing controlled release of drugto a patient includes (i) deploying a drug delivery device in thepatient, the device comprising a closed drug reservoir lumen bounded bya first wall structure and a hydrophilic second wall structure; and (ii)releasing a drug from the drug reservoir lumen via diffusion through thesecond wall structure, wherein the first wall structure is impermeableto the drug, and the second wall structure is permeable to the drug. Inone embodiment, the first wall structure is a cylindrical tube and thesecond wall structure is an end wall disposed at at least one end of thecylindrical tube, or the first wall structure and the second wallstructure are adjacent one another and together form a cylindrical tube.For example, the device may include any features, or combinations offeatures, described herein.

The device may be implanted non-surgically and may deliver drug forseveral days, weeks, months, or more after the implantation procedurehas ended. In one embodiment, implanting the drug delivery device in thepatient includes inserting the device into a body cavity or lumen of thepatient via a deployment instrument. For example, the device may bedeployed through a deployment instrument, such as a catheter orcystoscope, positioned in a natural lumen of the body, such as theurethra, or into a body cavity, such as the bladder. The deploymentinstrument typically is removed from the body lumen while the drugdelivery device remains in the bladder or other body cavity for aprescribed treatment period.

The device, in some embodiments, may be deployed into the bladder of apatient in an independent procedure or in conjunction with anotherurological or other procedure or surgery, either before, during, orafter the other procedure. The device may release one or more drugs thatare delivered to local and/or regional tissues for therapy orprophylaxis, either peri-operatively, post-operatively, or both.

In one example, the device is implanted by passing the drug deliverydevice through a deployment instrument and releasing the device from thedeployment instrument into the body. In cases in which the device isdeployed into a body cavity such as the bladder, the device assumes aretention shape, such as an expanded or higher profile shape, once thedevice emerges from the deployment instrument into the cavity. Thedeployment instrument may be any suitable lumen device, such as acatheter, e.g., a urethral catheter, or cystoscope. These terms are usedinterchangeably herein, unless otherwise expressly indicated. Thedeployment instrument may be a commercially available device or a devicespecially adapted for the present drug delivery devices. In oneembodiment, deploying the drug delivery device in the patient includes(i) elastically deforming the device into a relatively straightenedshape; (ii) inserting the device through the patient's urethra; and(iii) releasing the device into the patient's bladder such that itassumes a retention shape suited to retain the device within thebladder.

The drug delivery device may be passed through the deploymentinstrument, driven by a stylet or flow of lubricant or other fluid, forexample, until the drug delivery device exits a lumen of the instrumentas passes into the bladder. Thus, the device may be implanted into thebladder of a male or female human patient in need of treatment, eitheradult or child.

Once deployed in vivo, the device subsequently may release one or moredrugs for the treatment of one or more conditions, locally to one ormore tissues at the deployment site and/or regionally to other tissuesdistal from the deployment site. The release may be controlled and mayrelease the drug in an effective amount over an extended period.Thereafter, the device may be removed, resorbed, excreted, or somecombination thereof. In certain embodiments, the device resides in thebladder releasing the drug over a predetermined period, such as twoweeks, three weeks, four weeks, a month, or more.

Once implanted, the device may provide extended, continuous,intermittent, or periodic release of a desired quantity of drug over adesired, predetermined period. In embodiments, the device can deliverthe desired dose of drug over an extended period, such as 12 hours, 24hours, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90days, or more. The rate of delivery and dosage of the drug can beselected depending upon the drug being delivered and the disease orcondition being treated. In one embodiment, a rate of release of thedrug from the drug delivery device is zero order over at least 36 hours.In one embodiment, a rate of the release of the drug from the drugdelivery device is essentially zero order over at least 7 days.

In certain embodiments, elution of drug from the device occurs followingdissolution of the drug within the device. Bodily fluid enters thedevice, contacts the drug and solubilizes the drug, and thereafter thedissolved drug diffuses from the device. For example, the drug may besolubilized upon contact with urine in cases in which the device isimplanted in the bladder. In one embodiment, releasing the drug from thedevice includes solubilizing the drug with water imbibed through thesecond wall structure, or both the first and second wall structures.

The device may be used to treat interstitial cystitis, radiationcystitis, pelvic pain, bladder inflammation, overactive bladdersyndrome, bladder cancer, neurogenic bladder, neuropathic ornon-neuropathic bladder-sphincter dysfunction, infection, post-surgicalpain or other diseases, disorders, and conditions treated with drugsdelivered to the bladder. The device may release drug locally to thebladder and regionally to other sites near the bladder. The device maydeliver drugs that improve bladder function, such as bladder capacity,compliance, and/or frequency of uninhibited contractions, that reducepain and discomfort in the bladder or other nearby areas, or that haveother effects, or combinations thereof. The bladder-deployed device alsomay deliver a therapeutically effective amount of one or more drugs toother genitourinary sites within the body, such as other locationswithin urological or reproductive systems of the body, including thekidneys, urethra, ureters, penis, testes, seminal vesicles, vasdeferens, ejaculatory ducts, prostate, vagina, uterus, ovaries, orfallopian tubes, among others or combinations thereof. For example, thedrug delivery device may be used in the treatment of kidney stones orfibrosis, erectile dysfunction, among other diseases, disorders, andconditions.

In one embodiment, the device may have two payloads of drug that arereleased at different times. The first payload may be adapted forrelatively quick release, while the second payload may be adapted formore continuous release.

Subsequently, the device may be retrieved from the body, such as incases in which the device is non-resorbable or otherwise needs to beremoved. Retrieval devices for this purpose are known in the art or canbe specially produced. The device also may be completely or partiallybioerodible, resorbable, or biodegradable, such that retrieval isunnecessary, as either the entire device is resorbed or the devicesufficiently degrades for expulsion, for example, from the bladderduring urination. The device may not be retrieved or resorbed until someof the drug, or preferably most or all of the drug, has been released.If needed, a new drug-loaded device may subsequently be implanted,during the same procedure as the retrieval or at a later time.

The present invention may be further understood with reference to thefollowing non-limiting examples.

Example 1

Pouches formed of Tecophilic™ film and loaded with gemcitabine (GEM)were tested in vitro for drug permeation. The effect of gammairradiation on these pouches was also studied.

The pouches were made of HP-93A-100 and HP-60D-60 films with thicknessof 0.5 mm (films provided by Lubrizol). These thermoplasticpolyurethanes (TPUs) were selected for their biocompatibility andability to absorb equilibrium water content up to 100% of the weight ofdry resin, as well as other properties. The material properties of thefilm materials used are given below in Table 1.

TABLE 1 Tecophilic ™ HP-93A-100 and HP-60D-60 Film Material PropertiesASTM HP-60D-60 HP-93A100 Durometer (Shore D2240 41D 83A Hardness)Specific Gravity D792 1.15 1.13 Flexural Modulus D790 4000 2900 (psi)Ultimate Tensile (psi) D412 Dry 8300 2200 Wet 3100 1400 UltimateElongation D412 Dry 500 1040 Wet 300 620 Water Absorption (%) 60 100

Each pouch was made out of 2 films which were heat-sealed at all fouredges of each pouch after loading each pouch with a single tablet ofgemcitabine HCl or base formulated as follows:

(1) Gemcitabine HCl: 89% GEM HCl, 10% Isomalt, 1% Lubritab (waterinsoluble), or

(2) Gemcitabine Base: 90% GEM Base, 5% PEG 8k, 5% PVP.

Some of the pouches were gamma irradiated (25 kGy). The pouches werethen placed into 21 mL DI water at 37° C. Thereafter, at each timepoint, 5× inversion, 1 mL sample was taken out followed by a 1 mL DIwater refill.

The cumulative amounts (in mg FBE or Free Base Equivalent) and percentamounts of drug released are illustrated in FIGS. 13-24. The resultsshow that gemcitabine, in either HCl or base form, permeated 0.5 mmTecophilic™ film. Faster release was observed with HP-93A-100 (lowerdurometer) than with HP-60D-60 (higher durometer). Gemcitabine HCl(higher solubility) was released faster than gemcitabine base (lowersolubility). No negative effect from the gamma irradiation was observed.

Example 1A

Pouches constructed as in Example 1 were made, except each was loadedwith 1 gemcitabine (GEM) HCl tablet and 4 tablets of urea. The poucheswere then placed into 21 mL DI water at 37° C. Thereafter, at each timepoint, 5× inversion, 1 mL sample was taken out followed by a 1 mL DIwater refill.

The percent amounts of drug and urea released from the samples areillustrated in Tables 2-4 below. The results show that the gemcitabineand urea permeated 0.5 mm Tecophilic™ film in one day. Faster releasewas observed with HP-93A-100 (lower durometer) than with HP-60D-60(higher durometer).

TABLE 2 Sample Compositions GEM FBE Urea Sealed Area Sample (mg) (mg)(cm × cm) HP-60D-60 (1) 21 129 1.7 × 2.6 HP-60D-60 (2) 20 129 1.6 × 2.5HP-93A-100 (1) 21 134 1.6 × 2.9 HP-93A-100 (2) 22 120 1.5 × 2.7

TABLE 3 Percent Amount Gemcitabine Released (%) at Various Times Sample2 hour 1 day 2 day HP-60D-60 (1) 0 95 96 HP-60D-60 (2) 0 92 96HP-93A-100 (1) 1 91 92 HP-93A-100 (2) 4 93 94

TABLE 4 Percent Amount Urea Released (%) as Various Times Sample 2 hour1 day 2 day HP-60D-60 (1) 13 99 100 HP-60D-60 (2) 12 99 100 HP-93A-100(1) 61 98 99 HP-93A-100 (2) 62 99 99

Example 1B

Squares (0.5 inch×0.5 in) of HP-93A-100 and HP-60D-60 films withthickness of 0.020″ (films provided by Lubrizol) were cut and placedinto 50 mL DI water at 37° C. The mass of each film was measured at T=0and again at T=1 day, in order to measure water absorption of the film.The areas of each film were also measured at T=0 and again at T=1 day,in order to measure the increase in area of the film due to waterabsorption. The results are shown in Table 5 below The HP-93A-100 (lowerdurometer) was observed to increase in mass and water-swell, or expand,in area more than the HP-60D-60 (higher durometer) did.

TABLE 5 Mass and Area Measurements of Dry and Wet Samples Dry Wet % DryWet % Mass Mass Mass Area Area Area Sample (mg) (mg) Increase (cm²)(cm²) Increase HP-93A-100(1) 89 162 82 1.6 2.6 64 HP-93A-100(2) 88 16082 1.6 2.6 64 HP-60D-60(1) 80 117 46 1.6 2.0 25 HP-60D-60(2) 91 135 491.6 2.0 25

Example 2

A silicone tube made of MED-4750 (Nusil) had the dimensions of 2.64 mmID and 0.20 mm wall thickness. Multiple gemcitabine HCl tablets with 2.6mm OD were loaded into the silicone tube with a total gemcitabine HClpayload of approximately 380 mg. Each end of the tablets drug core had a0.5 mm thickness disk made of HP-60D-60 (Tecophilic™ ThermoplasticPolyurethanes). The diameters of the disks are shown in FIG. 25. Thedisks were oversized compared with silicone tube ID, and so they werefrictionally fit into the tube. The layout of each device in thesilicone tube was: Disk-Tablets-Disk. Three devices were built andplaced in deionized water at 37° C. for in vitro release experiment.Results are shown in FIG. 25. Y-axis indicates gemcitabine release rate,and the unit is mg FBE (Free Base Equivalent) per day.

Example 3

A silicone tube made of MED-4750 (Nusil) had dimensions of 2.64 mm IDand 0.20 mm wall thickness. Multiple gemcitabine HCl tablets with 2.6 mmOD were loaded into the silicone tube with a total gemcitabine HClpayload of approximately 200 mg. Each device had a disk made ofHP-93A-100 (Tecophilic™ Thermoplastic Polyurethanes) at each end of thetablets drug core. The dimensions of each disk were approximately 0.5 mmthickness and 3.0 mm OD. The OD (3.0 mm) of the disks was larger thanthe silicone tube ID (2.64 mm), and so the disks were frictionally fitin the silicone tube. In addition, there was a silicone washer, made ofMED-4780 (Nusil), located next to each disk with silicone adhesive(MED3-4213) applied around the washer, to stabilize the outwardmigration of the disk. The silicone washer had the dimensions of ID, OD,and the length of approximately 2.5 mm, 3.2 mm, and 2 mm, respectively.The layout of each device in the silicone tube was: SiliconeWasher-Disk-Tablets-Disk-Silicone Washer. Six devices were built andplaced in deionized water at 37° C. for in vitro release experiment.They were divided into two groups. In one group, the releasing jars wererotated in the rotator at 4 rpm (labeled ‘Rotator’) as opposed to theother group (labeled ‘Static’). Results are shown in FIG. 26. Each errorbar shown below is standard deviation around the mean (n=3 for eachgroup). Y-axis indicates gemcitabine release rate, and the unit is mgFBE (Free Base Equivalent) per day.

Example 4

A silicone tube made of MED-4750 (Nusil) had dimensions of 2.64 mm IDand 0.20 mm wall thickness. Multiple gemcitabine HCl tablets with 2.6 mmOD were loaded into the silicone tube with a total gemcitabine HClpayload of approximately 97 mg. The device had a disk made of HP-93A-100(Tecophilic™ Thermoplastic Polyurethanes) at one of the drug core andthe other end was sealed by silicone adhesive. The dimensions of eachdisk were approximately 0.5 mm thickness and 3.0 mm OD. The OD (3.0 mm)of the disks was larger than the silicone tube ID (2.64 mm), and so thedisks were frictionally fit in the silicone tube. In addition, therewere polyimide washers located at both sides of the disk. The dimensionsof the polyimide washers were 2.67 mm ID, 0.064 mm wall, andapproximately 1-2 mm length. The inner washer was filled with a tabletso that the disk was initially in contact with the tablet. The layout ofeach device in the silicone tube was: Polyimide OuterWasher-Disk-Polyimide Inner Washer-Tablets-Sealed. Three devices werebuilt and placed in deionized water at 37° C. for in vitro releaseexperiment. Results are shown in FIG. 27. Each error bar shown below isstandard deviation around the mean (n=3). Y-axis indicates gemcitabinerelease rate, and the unit is mg FBE (Free Base Equivalent) per day.

Example 5

There were three experimental groups tested: 1) one module device withthe releasing jar being rotated in the rotator at 4 rpm (‘Rotator’), 2)one module device without the jar rotated (‘Static’), and 3) four moduledevice without the jar rotated (‘Static’). Each module is comprised ofsilicone tube made of MED-4750 (Nusil) with the dimensions of 2.64 mm IDand 0.20 mm wall thickness. Multiple gemcitabine HCl tablets with 2.6 mmOD were loaded into the silicone tube with each module having a totalgemcitabine HCl payload of approximately 190 mg. The tablet formulationwas 90% gemcitabine HCl, 5% PVP, 2.5% Neusilin, and 2.5% magnesiumstearate. Each module had a disk made of HP-93A-100 (Tecophilic™Thermoplastic Polyurethanes) at each end of the tablet drug core. Thedimensions of each disk were approximately 0.5 mm thickness and 3.0 mmOD. The OD (3.0 mm) of the disks was larger than the silicone tube ID(2.64 mm), and so the disks were frictionally fit in the silicone tube.Each module has a silicone outer washer, made of MED-4780 (Nusil),located next to each disk with silicone adhesive (MED3-4213) appliedaround the washer, to stabilize the outward migration of the disk. Thesilicone outer washer had the dimensions of ID, OD, and the length ofapproximately 2.5 mm, 3.2 mm, and 2 mm, respectively. In addition, eachmodule has a polyimide inner washer with 2.67 mm ID, 0.064 mm wall, andapproximately 4 mm length. The inner washer was filled with a tablet sothat the disk was initially in contact with the tablet. The layout ofeach module in the silicone tube was: Silicone OuterWasher-Disk-Polyimide Inner Washer-Tablets-Polyimide InnerWasher-Disk-Silicone Outer Washer.

The cumulative and percent amounts of drug released, as well as the drugrelease rate are illustrated in FIGS. 28-31: one module device (Static),one module device (Rotator), and four module device (Static) (n=3 pereach group). In FIG. 31, each error bar is standard deviation around themean and Y-axis indicates gemcitabine release rate, and the unit is mgFBE (Free Base Equivalent) per day. Some error bars are smaller thansymbols. There was no significant difference in gemcitabine release ratebetween release medium non-stirring group and stirring group (Static vsRotator). Also, the gemcitabine release rate of the 4-module device wasapproximately four times higher than that of the 1-module device.

Example 6

Gemcitabine HCl was tested in a four module device. Each module wascomprised of silicone tube made of MED-4750 (Nusil) with the dimensionsof 2.64 mm ID and 0.20 mm wall thickness. Multiple tablets with 2.6 mmOD were loaded into the silicone tube. The tablet formulation was 90%gemcitabine HCl, 5% PVP, 2.5% Neusilin, and 2.5% magnesium stearate.Tablet mass loaded in four module device was approximately 800 mg. Thesilicone tube had an additional lumen with 0.51 mm ID and 0.20 mm wallas in FIG. 5A and nitinol retention frame was inserted into the lumen.Each module had a disk made of HP-93A-100 (Tecophilic™ ThermoplasticPolyurethanes) at both ends of the tablet drug core. The dimensions ofeach disk were approximately 0.5 mm thickness and 3.0 mm OD. The OD (3.0mm) of the disk was larger than the silicone tube ID (2.64 mm), and sothe disk was frictionally fit in the silicone tube.

Each module had inner and outer silicone washers, made of MED-4780(Nusil), and located next to disks with silicone adhesive applied aroundthe washers to fix it in the silicone tube. The silicone outer washerhad the dimensions of ID, OD, and the length of approximately 2.5 mm,3.2 mm, and 2 mm, respectively, and the silicone inner washer had thedimensions of ID, OD, and the length of approximately 1.58 mm, 2.77 mm,and 2 mm, respectively. The layout of each module in the silicone tubewas: Silicone Outer Washer-Disk-Silicone Inner Washer-Tablets-SiliconeInner Washer-Disk-Silicone Outer Washer.

In vitro release experiment with three units (R204-4 to 6) was performedat 37° C. The release medium was deionized water, and time point sampleswere collected over 14 days. The cumulative amount of drug released andthe urine concentration of the samples were measured. The results areshown in FIG. 32. Each error bar is standard deviation around the mean(n=3). Some error bars are smaller than symbols.

The devices with the same design were tested in vivo with threeGöttingen minipigs. Each device was inserted into the bladder of eachanimal through the urethra non-surgically by cystoscope. The urineconcentration of gemcitabine plus 2′,2′-difluoro-2′-deoxyuridine (dFdU),its terminal metabolite, was measured over 8 day period.

The results are shown in FIG. 33. After the 8 day study, each device wasremoved through the urethra non-surgically by cystoscope and forceps.

Example 7

Trospium chloride was tested in a single module device. A module wascomprised of silicone tube made of MED-4750 (Nusil) with the dimensionsof 2.64 mm ID and 0.20 mm wall thickness. Multiple trospium tablets with2.6 mm OD were loaded into the silicone tube. The tablet formulation wastrospium chloride without any excipient, and tablet mass loaded in eachmodule was approximately 330 mg and the tablet core length was 5 cmlong. The silicone tube had an additional lumen with 0.51 mm ID and 0.20mm wall and nitinol retention frame was inserted into the lumen. Eachmodule had a disk made of HP-93A-100 (Tecophilic™ ThermoplasticPolyurethanes) at one end of the tablet drug core while the other endwas sealed by silicone adhesive. The dimensions of each disk wereapproximately 0.5 mm thickness and 3.0 mm OD. The OD (3.0 mm) of thedisk was larger than the silicone tube ID (2.64 mm), and so the disk wasfrictionally fit in the silicone tube. Each module had a siliconewasher, made of MED-4780 (Nusil), and located next to each disk withsilicone adhesive applied around the washer. The silicone washer had thedimensions of ID, OD, and the length of approximately 2.5 mm, 3.2 mm,and 2 mm, respectively. The layout of each module in the silicone tubewas: Silicone Washer-Disk-Tablets-Sealed.

In vitro release experiment with three units was performed at 37° C. Therelease medium was 150 mM ammonium acetate buffer at pH 4.5 from Day 0to Day 14. Then, from Day 14 to Day 21, each unit from L104-1 to L104-3was moved to one of artificial urines with varying pHs and osmolalities:pH 8 and 1000 mmol/kg, pH 4 and 450 mmol/kg, and pH 8 and 450 mmol/kg,respectively. Then, from Day 21, the release medium was back to 150 mMammonium acetate buffer at pH 4.5 for all units. The cumulative amountof drug released is shown in FIG. 34.

Example 8

Trospium chloride was tested in a single module device. A module wascomprised of silicone tube made of MED-4750 (Nusil) with the dimensionsof 2.64 mm ID and 0.20 mm wall thickness. Multiple trospium tablets with2.6 mm OD were loaded into the silicone tube. The tablet formulation wastrospium chloride (80.75% w/w), Plasdone K-29/32 (4.25% w/w), PROSOLVSMCC 50 (14.0% w/w), and magnesium stearate (1% w/w) and tablet massloaded in each module was approximately 900 mg and the tablet corelength was 14 cm long. The silicone tube had an additional lumen with0.51 mm ID and 0.20 mm wall and nitinol retention frame was insertedinto the lumen. Each module had a disk made of HP-93A-100 (Tecophilic™Thermoplastic Polyurethanes) at one end of the tablet drug core whilethe other end was sealed by silicone adhesive. The dimensions of eachdisk were approximately 0.5 mm thickness and 3.0 mm OD. The OD (3.0 mm)of the disk was larger than the silicone tube ID (2.64 mm), and so thedisk was frictionally fit in the silicone tube. Each module had asilicone washer, made of MED-4780 (Nusil), and located next to each diskwith silicone adhesive applied around the washer to fix it. The siliconewasher had the dimensions of ID, OD, and the length of approximately 2.5mm, 3.2 mm, and 2 mm, respectively. The layout of each module in thesilicone tube was: Silicone Washer-Disk-Tablets-Sealed.

In vitro release experiment was performed at 37° C. and the releasemedia was 150 mM ammonium acetate buffer at pH 4.5, and samples werecollected over a 3 month period. The release media was changed to freshone every two weeks. The results are given in FIG. 35. Each error bar isstandard deviation around the mean (n=3). Some error bars are smallerthan symbols.

Example 9

Lidocaine HCl was tested in a single module system. A module wascomprised of silicone tube made of MED-4750 (Nusil) with the dimensionsof 2.64 mm ID and 0.20 mm wall thickness. Multiple lidocaine HCl tabletswith 2.64 mm OD were loaded into the silicone tube. The tabletformulation was lidocaine hydrochloride monohydrate (89.5% w/w),Plasdone K-29/32 (2.5% w/w), and Polyglykol 8000 PF (8.0% w/w), andtablet mass loaded in each module was approximately 320 mg and thetablet core length was 5 cm long. Each module had a disk made ofHP-93A-100 (Tecophilic™ Thermoplastic Polyurethanes) at one end of thetablet drug core while the other end was sealed by silicone adhesive.The dimensions of each disk were approximately 0.5 mm thickness and 3.0mm OD. The OD (3.0 mm) of the disk was larger than the silicone tube ID(2.64 mm), and so the disk was frictionally fit in the silicone tube.Each module had a silicone washer, made of MED-4780 (Nusil), and locatednext to each disk with silicone adhesive applied around the washer tofix it. The silicone washer had the dimensions of ID, OD, and the lengthof approximately 2.5 mm, 3.2 mm, and 2 mm, respectively. The layout ofeach module in the silicone tube was: SiliconeWasher-Disk-Tablets-Sealed.

In vitro release experiment was performed in deionized water at 37° C.,and samples were collected over 8 day time period. The results are givenin FIG. 36. Each error bar is standard deviation around the mean (n=2).Some error bars are smaller than symbols.

Example 10

Lidocaine HCl was tested in a side-hole device with the followinglayout. Inner silicone tube with two holes—Hydrophilic polymerband—Outer silicone sleeve with two holes. The inner silicone tube wasmade of MED-4750 (Nusil) with the dimensions of 1.52 mm ID, 0.2 mm wall,and contained the lidocaine tablets. The formulation of the tablets waslidocaine hydrochloride monohydrate (89.5% w/w), Plasdone K-29/32 (2.5%w/w), and Polyglykol 8000 PF (8.0% w/w). The tablet mass loaded wasapproximately 105 mg and the tablet core length was 5 cm. Two holes hadapproximately 1.2 mm diameter, and were created by manual punch in bothinner silicone tube and outer silicone sleeve. Two punched holes werelocated opposite to each other. The hydrophilic polymer band was made ofHP-93A-100 (Tecophilic™ Thermoplastic Polyurethanes) with 2.64 mm OD,0.2 mm wall, and 1 cm length. Outer silicone sleeve had 3.05 mm ID, 0.2mm wall, and 2 cm length. Silicone adhesive was applied between theinner silicone tube and outer silicone sleeve. The holes in the innersilicone tube and the outer silicone sleeve were aligned.

In vitro release experiment was performed in deionized water at 37° C.,and samples were collected over 7 day period. The results are given inFIG. 37. Each error bar is standard deviation around the mean (n=2).Some error bars are smaller than symbols.

Publications cited herein and the materials for which they are cited arespecifically incorporated by reference. Modifications and variations ofthe methods and devices described herein will be obvious to thoseskilled in the art from the foregoing detailed description. Suchmodifications and variations are intended to come within the scope ofthe appended claims.

We claim:
 1. An intravesical drug delivery device comprising: a housinghaving a closed drug reservoir lumen bounded by a first wall structureand a hydrophilic second wall structure, wherein the drug reservoirlumen is closed such that no aperture extends through the housing; andone or more solid drug units comprising a high weight fraction of adrug, the one or more solid drug units being contained in the drugreservoir lumen, wherein the first wall structure is impermeable to thedrug, and the second wall structure is formed of a material that ispermeable to the drug, wherein the first wall structure is an elongatedcylindrical tube and the second wall structure is an end wall in theform of a disk stabilized in a lumen of the elongated cylindrical tube,and wherein the first and second wall structures are water permeable,such that the device is configured to release solubilized drug from theclosed drug reservoir lumen by diffusion through only the materialforming the second wall structure upon the one or more solid drug unitsbeing contacted by water that enters the drug reservoir lumen throughthe first and second wall structures.
 2. The device of claim 1, whereinthe device is configured for intravesical insertion and retention. 3.The device of claim 2, wherein the device is elastically deformablebetween a relatively straightened shape suited for insertion through aurethra of a patient and into a bladder of the patient and a retentionshape suited to retain the device within the bladder.
 4. The device ofclaim 3, further comprising a retention frame lumen and a retentionframe disposed therein.
 5. The device of claim 1, wherein the first wallstructure comprises silicone.
 6. The device of claim 1, wherein thesecond wall structure comprises a thermoplastic polyurethane.
 7. Thedevice of claim 1, wherein the disk is sandwiched between an innerwasher and an outer washer.
 8. The device of claim 1, wherein the drugis a low solubility drug.
 9. The device of claim 1, wherein the drug isa high solubility drug.
 10. The device of claim 1, wherein the drugcomprises lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin,oxaliplatin, trospium, tolterodine, oxybutynin, or mitomycin C.
 11. Thedevice of claim 1, wherein the device is configured to be free floatingin a patient's bladder upon deployment.
 12. The device of claim 1,wherein: the first wall structure comprises silicone having a Shorehardness of from 50A to 70A, and the second wall structure comprises athermoplastic polyurethane having a Shore hardness of from 70A to 65D.13. An intravesical drug delivery device, comprising: a housing having aclosed drug reservoir lumen bounded by a first wall structure and ahydrophilic second wall structure, such that no aperture extends throughthe housing, wherein the first wall structure is an elongatedcylindrical tube and the second wall structure is an end wall disposedat one end or both ends of the cylindrical tube, and wherein the firstand second wall structures are water permeable; and a drug in solid formcontained in the drug reservoir lumen, wherein the second wall structurecomprises a thermoplastic polyurethane, wherein the device isconfigured, upon deployment in a bladder of a patient, to permit waterto diffuse into the closed drug reservoir lumen and solubilize the drugand then to permit the solubilized drug to diffuse through thethermoplastic polyurethane forming the second wall structure but notthrough the first wall structure, which is impermeable to the drug, andwherein the device is elastically deformable between a relativelystraightened shape suited for insertion through a urethra of the patientand into the bladder and a retention shape suited to retain the devicewithin the bladder.
 14. The device of claim 13, further comprising aretention frame lumen and a retention frame disposed therein.
 15. Thedevice of claim 13, wherein the first wall structure comprises silicone.16. The device of claim 15, wherein the silicone has a Shore hardness offrom 50A to 70A.
 17. The device of claim 16, wherein the second wallstructure comprises a thermoplastic polyurethane having a Shore hardnessof from 70A to 65D.
 18. The device of claim 13, wherein the second wallstructure is in the form of a disk stabilized in a lumen of theelongated cylindrical tube.
 19. The device of claim 18, wherein the diskis sandwiched between an inner washer and an outer washer.